First-in-class positron emission tomography tracer for the glucagon receptor
Abstract The glucagon receptor (GCGR) is emerging as an important target in anti-diabetic therapy, especially as part of the pharmacology of dual glucagon-like peptide-1/glucagon (GLP-1/GCG) receptor agonists. However, currently, there are no suitable biomarkers that reliably demonstrate GCG recepto...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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SpringerOpen
2019-02-01
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| Series: | EJNMMI Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13550-019-0482-0 |
| _version_ | 1819125591645880320 |
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| author | Irina Velikyan Torsten Haack Martin Bossart Andreas Evers Iina Laitinen Philip Larsen Oliver Plettenburg Lars Johansson Stefan Pierrou Michael Wagner Olof Eriksson |
| author_facet | Irina Velikyan Torsten Haack Martin Bossart Andreas Evers Iina Laitinen Philip Larsen Oliver Plettenburg Lars Johansson Stefan Pierrou Michael Wagner Olof Eriksson |
| author_sort | Irina Velikyan |
| collection | DOAJ |
| description | Abstract The glucagon receptor (GCGR) is emerging as an important target in anti-diabetic therapy, especially as part of the pharmacology of dual glucagon-like peptide-1/glucagon (GLP-1/GCG) receptor agonists. However, currently, there are no suitable biomarkers that reliably demonstrate GCG receptor target engagement. Methods Two potent GCG receptor peptide agonists, S01-GCG and S02-GCG, were labeled with positron emission tomography (PET) radionuclide gallium-68. The GCG receptor binding affinity and specificity of the resulting radiopharmaceuticals [68Ga]Ga-DO3A-S01-GCG and [68Ga]Ga-DO3A-S02-GCG were evaluated in HEK-293 cells overexpressing the human GCG receptor and on frozen hepatic sections from human, non-human primate, and rat. In in vivo biodistribution, binding specificity and dosimetry were assessed in rat. Results [68Ga]Ga-DO3A-S01-GCG in particular demonstrated GCG receptor-mediated binding in cells and liver tissue with affinity in the nanomolar range required for imaging. [68Ga]Ga-DO3A-S01-GCG binding was not blocked by co-incubation of a GLP-1 agonist. In vivo binding in rat liver was GCG receptor specific with low non-specific binding throughout the body. Moreover, the extrapolated human effective doses, predicted from rat biodistribution data, allow for repeated PET imaging potentially also in combination with GLP-1R radiopharmaceuticals. Conclusion [68Ga]Ga-DO3A-S01-GCG thus constitutes a first-in-class PET tracer targeting the GCG receptor, with suitable properties for clinical development. This tool has potential to provide direct quantitative evidence of GCG receptor occupancy in humans. |
| first_indexed | 2024-12-22T07:42:35Z |
| format | Article |
| id | doaj.art-319da706f4c14a3d943426510f998c0c |
| institution | Directory Open Access Journal |
| issn | 2191-219X |
| language | English |
| last_indexed | 2024-12-22T07:42:35Z |
| publishDate | 2019-02-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | EJNMMI Research |
| spelling | doaj.art-319da706f4c14a3d943426510f998c0c2022-12-21T18:33:42ZengSpringerOpenEJNMMI Research2191-219X2019-02-019111310.1186/s13550-019-0482-0First-in-class positron emission tomography tracer for the glucagon receptorIrina Velikyan0Torsten Haack1Martin Bossart2Andreas Evers3Iina Laitinen4Philip Larsen5Oliver Plettenburg6Lars Johansson7Stefan Pierrou8Michael Wagner9Olof Eriksson10PET Centre, Centre for Medical Imaging, Uppsala University HospitalSanofi-Aventis Deutschland GmbH, Industriepark HöchstSanofi-Aventis Deutschland GmbH, Industriepark HöchstSanofi-Aventis Deutschland GmbH, Industriepark HöchstSanofi-Aventis Deutschland GmbH, Industriepark HöchstSanofi-Aventis Deutschland GmbH, Industriepark HöchstInstitute of Medicinal Chemistry, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Antaros Medical ABAntaros Medical ABSanofi-Aventis Deutschland GmbH, Industriepark HöchstAntaros Medical ABAbstract The glucagon receptor (GCGR) is emerging as an important target in anti-diabetic therapy, especially as part of the pharmacology of dual glucagon-like peptide-1/glucagon (GLP-1/GCG) receptor agonists. However, currently, there are no suitable biomarkers that reliably demonstrate GCG receptor target engagement. Methods Two potent GCG receptor peptide agonists, S01-GCG and S02-GCG, were labeled with positron emission tomography (PET) radionuclide gallium-68. The GCG receptor binding affinity and specificity of the resulting radiopharmaceuticals [68Ga]Ga-DO3A-S01-GCG and [68Ga]Ga-DO3A-S02-GCG were evaluated in HEK-293 cells overexpressing the human GCG receptor and on frozen hepatic sections from human, non-human primate, and rat. In in vivo biodistribution, binding specificity and dosimetry were assessed in rat. Results [68Ga]Ga-DO3A-S01-GCG in particular demonstrated GCG receptor-mediated binding in cells and liver tissue with affinity in the nanomolar range required for imaging. [68Ga]Ga-DO3A-S01-GCG binding was not blocked by co-incubation of a GLP-1 agonist. In vivo binding in rat liver was GCG receptor specific with low non-specific binding throughout the body. Moreover, the extrapolated human effective doses, predicted from rat biodistribution data, allow for repeated PET imaging potentially also in combination with GLP-1R radiopharmaceuticals. Conclusion [68Ga]Ga-DO3A-S01-GCG thus constitutes a first-in-class PET tracer targeting the GCG receptor, with suitable properties for clinical development. This tool has potential to provide direct quantitative evidence of GCG receptor occupancy in humans.http://link.springer.com/article/10.1186/s13550-019-0482-0GlucagonGCGGLP-1 receptorDual agonistType 2 diabetes |
| spellingShingle | Irina Velikyan Torsten Haack Martin Bossart Andreas Evers Iina Laitinen Philip Larsen Oliver Plettenburg Lars Johansson Stefan Pierrou Michael Wagner Olof Eriksson First-in-class positron emission tomography tracer for the glucagon receptor EJNMMI Research Glucagon GCG GLP-1 receptor Dual agonist Type 2 diabetes |
| title | First-in-class positron emission tomography tracer for the glucagon receptor |
| title_full | First-in-class positron emission tomography tracer for the glucagon receptor |
| title_fullStr | First-in-class positron emission tomography tracer for the glucagon receptor |
| title_full_unstemmed | First-in-class positron emission tomography tracer for the glucagon receptor |
| title_short | First-in-class positron emission tomography tracer for the glucagon receptor |
| title_sort | first in class positron emission tomography tracer for the glucagon receptor |
| topic | Glucagon GCG GLP-1 receptor Dual agonist Type 2 diabetes |
| url | http://link.springer.com/article/10.1186/s13550-019-0482-0 |
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